Anticancer drug combinations have attracted much attention and have been extensively explored in clinical studies for the treatment of various types of cancer. Due to the heterogeneity of a tumor, cancer cells exist at different cell cycles. Delivery of multiple therapeutic agents using a single carrier system can suppress the cancer growth, since the drugs can have specific activity based on the different growth cycle of a cancer cell. A drug cocktail, such as a combination of drugs with different anticancer mechanisms that act synergistically, should exhibit superior response and patient survival rate than any single agent. However, the translation of this theoretical advantage to benefit the patient is hindered by their associated side effects, which can include (i) the potent toxic drug combination can damage normal cells while it kills cancer cells, (ii) the potential drug-drug interaction can deteriorate patient health condition, and (iii) the consequence of side effect results in poor patient compliance.
In order to enhance the efficacy of anticancer drugs while attenuating their associated side effects, nanotechnology was introduced into the treatment of cancer. Nanoparticle related cancer targeting is mainly achieved by passive accumulation of drug-loaded nanoparticles through the leaky blood capillaries in the tumor tissue. It has been shown that those vasculature pore sizes could be as large as 400 nm, which allows the extravagation of nanoparticles to the cancer tissues. In addition, lymphatic deficiency develops during cancer's progression; as a consequence, the lymphatic drainage of the nanoparticles from the tumor tissue is inadequate. The synergic effect of the above mentioned characteristics of tumor tissue results in the passive accumulation of nano-sized particles. This phenomenon is referred to as enhanced permeability and retention effect (EPR) of cancer. It has been demonstrated that by taking advantage of the EPR effect, nanoparticles can preferentially deliver drugs to cancer tissues, and therefore significantly enhance the therapeutic efficacy while substantially reducing drug side effects. As such, a need exists for a nanocarrier that is stable in a physiological environment during circulation while intracellularly releasing its payload in a timely manner after entering the cancer cell.